Substituted aromatic ethers as inhibitors of glycine transport

ABSTRACT

This invention relates to a series of substituted aromatic ethers of the formula I  
                 
 
     wherein ring A and X and Y are defined as in the specification, that exhibit activity as glycine transport inhibitors, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their use for the enhancement of cognition and the treatment of the positive and negative symptoms of schizophrenia and other psychoses in mammals, including humans.

[0001] This application claims the benefit of U.S. Ser. No. 60/299,827,filec Jun. 21, 2001, the contents of which are incorporated herein byreference.

BACKGROUND

[0002] The present invention relates to aromatic ethers containing apendant amino acid side chain and to pharmaceutical compositionscontaining them and to their use in the treatment of central nervoussystem disorders, cognitive disorders, schizophrenia, dementia and otherdisorders in mammals, including humans. These compounds exhibit activityas inhibitors of the glycine type-1 transporter.

[0003] Schizophrenia, a progressive neurological disease, is manifestedin its early stages as thought disorders such as hallucinations,paranoid delusions, and bizarre thought patterns, collectively known aspositive symptoms. These easily recognizable symptoms gave the diseasethe historical name “madness”. As the disease progresses, negativesymptoms, such as social withdrawal and anhedonia, and cognitivesymptoms such as dementia become more apparent. Only about one-third ofschizophrenic patients can be treated successfully and returned tosociety, while the remainder are generally institutionalized. The burdenon society of this devastating illness and the toll it takes on familymembers of affected patients make it one of the most costly of all CNSdiseases.

[0004] Pharmacological treatment for schizophrenia has traditionallyinvolved blockade of the dopamine system, which is thought to beresponsible for its positive symptoms. Such treatment, however, ignoresthe negative and cognitive aspects of the disease. Anotherneurotransmitter system believed to play a role in schizophrenia is theglutamate system, the major excitatory transmitter system in the brain.This hypothesis is based on the observation that blockade of theglutamate system by compounds such as PCP (“angel dust”) can replicatemany of the symptoms of schizophrenia, including its positive, negative,and cognitive aspects. If schizophrenia involves a deficit ofglutamatergic transmission, augmentation of the glutamate system, andspecifically the NMDA receptor, may be beneficial. While glutamate isthe principle agonist at NMDA receptors, glycine is required as aco-agonist to set the “tone” of the receptor for its response toglutamate. Enhancing this “tone” by increasing the effect of glycinewould augment NMDA neurotransmission, and provide potential benefit inthe treatment of schizophrenia.

[0005] A specific mechanism for augmenting the glycinergic “tone” of theNMDA receptor was disclosed recently by Bergeron, et al. (Proc. Natl.Acad. Sci. USA, 95, 15730, (1998)). This group showed that a specificand potent inhibitor of the glycine type-1 transporter (GlyT1)responsible for removing glycine from the synapse at the NMDA receptor,termed NFPS (WO 97/45115), can enhance NMDA receptor function. Forexample, NFPS increased the post synaptic current driven by the NMDAreceptor, an effect blocked by both a specific NMDA-site antagonist anda glycine-site antagonist. Even though glycine levels in the brain arehigh relative to the amount required to act as an NMDA receptorco-agonist, this work shows that GlyT1 removes glycine efficiently atthe synapse, and that inhibition of GlyT1 can augment NMDA receptorfunction. The authors establish the feasibility of using a GlyT1inhibitor as a treatment for schizophrenia through its augmentation ofglutamatergic neurotransmission.

SUMMARY OF THE INVENTION

[0006] The present invention relates to a series of substituted aromaticethers of the formula

[0007] wherein

[0008] ring A is phenyl, naphthyl, benzothienyl, benzofuranyl, orpyridyl; or ring A is a monocyclic aryl or heteroaryl ring containingfrom zero to four heteroatoms and not containing any adjacent ringoxygen atoms; or ring A is a bicyclic aryl or heteroaryl ring containingfrom zero to five heteroatoms and not containing any adjacent ringoxygen atoms; and

[0009] X and Y are each, independently, (C₁-C₆) alkyl optionallysubstituted with from one to seven fluorine atoms; (C₁-C₆)alkoxyoptionally substituted with from one to seven fluorine atoms, whereinthe number of fluorine substituents on the foregoing (C₁-C₆) alkyl and(C₁-C₆) alkoxy groups can not exceed the number of positions in suchgroups that are available for substitution; carboxy;carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl; sulfonyl;halo; nitro; cyano; amino; (C₁-C₆) alkylamino and di[(C₁-C₆)alkyl]amino;

[0010] B is (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with 1 to7 fluorine atoms, or halogen;

[0011] and the pharmaceutically acceptable salts of such compounds.

[0012] In a preferred embodiment of this invention, ring A is selectedfrom phenyl, naphthyl benzofuranyl, benzothienyl, indanyl,tetrahydronaphthyl, dihydrobenzofuranyl, and dihydrobenzothiophenyl. Inanother preferred embodiment of this invention, X ispara-trifluoromethyl, para-methyl or para-chloro.

[0013] The present invention also relates to a compound having theformula:

[0014] wherein Y is (C₁-C₆)alkyl optionally substituted with from one toseven fluorine atoms; (C₁-C₆)alkoxy optionally substituted with from oneto seven fluorine atoms, wherein the number of fluorine substituents onthe foregoing (C₁-C₆)alkyl and (C₁-C₆) alkoxy groups can not exceed thenumber of positions in such groups that are available for substitution;carboxy; carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl;sulfonyl; halo; nitro; cyano; amino; (C₁-C₆) alkylamino anddi{(C₁-C₆)alkyl}amino;

[0015] wherein Z¹ and Z² are independently selected from O, NH, N—(C₁-C₅alkyl), and S; and n is an integer from 1 to about 3;

[0016] or a pharmaceutically acceptable salt thereof.

[0017] The present invention also relates to a compound having theformula:

[0018] wherein Y is (C₁-C₆)alkyl optionally substituted with from one toseven fluorine atoms; (C₁-C₆)alkoxy optionally substituted with from oneto seven fluorine atoms, wherein the number of fluorine substituents onthe foregoing (C₁-C₆)alkyl and (C₁-C₆) alkoxy groups can not exceed thenumber of positions in such groups that are available for substitution;carboxy; carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl;sulfonyl; halo; nitro; cyano; amino; (C₁-C₆) alkylamino anddi{(C₁-C₆)alkyl}amino;

[0019] wherein Z¹ and Z² are independently selected from O, NH, N—(C₁-C₅alkyl), and S; and n is an integer from 1 to about 3;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] Specific preferred embodiments of the invention include:

[0022] {Methyl-[3-(4-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0023](Methyl-{3-phenyl-3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0024](Methyl-{3-phenyl-3-[4-(3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0025] {Methyl-[3-phenyl-3-(4-p-tolyloxy-phenoxy)-propyl]-amino}-aceticacid

[0026]({3-[4-(4-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0027]({3-[4-(4-Chloro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0028](Methyl-{3-[4-(naphthalen-2-yloxy)-phenoxy]-3-phenyl-propyl}-amino)-aceticacid

[0029]({3-[4-(4-Isopropyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0030]({3-[4-(4-tert-Butyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0031](Methyl-{3-phenyl-3-[4-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0032]({3-[4-(3,4-Dimethyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0033]({3-[4-(Indan-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0034]({3-[4-(2,4-Difluoro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0035]({3-(4-Fluoro-phenyl)-3-[4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0036]{[3-[4-(2,4-Dimethyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0037]({3-(4-Fluoro-phenyl)-3-[4-(2,4,6-trimethyl-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0038](Methyl-{3-phenyl-3-[4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0039]({3-[4-(2,4-Dimethyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0040]{[3-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0041]{[3-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0042]({3-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0043]({3-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0044]{[3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0045]({3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0046]{[3-[4-(2,3-Dihydro-benzofuran-7-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0047]({3-[4-(2,3-Dihydro-benzofuran-7-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0048]{[3-[4-(Benzofuran-4-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0049]({3-[4-(2,3-Dihydro-benzofuran-4-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0050]{[3-[4-(2,3-Dihydro-benzofuran-4-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0051]{[3-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0052]({3-(4-Fluoro-phenyl)-3-[4-(4-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0053](Methyl-{3-phenyl-3-[4-(4-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0054]{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0055]({3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0056]({3-[4-(3-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0057]({3-(4-Fluoro-phenyl)-3-[4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0058](Methyl-{3-phenyl-3-[4-(3-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0059]({3-(4-Fluoro-phenyl)-3-[4-(3-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0060]({3-[4-(2-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0061]({3-(4-Fluoro-phenyl)-3-[4-(2-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0062]({3-[4-(3,4-Dimethoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0063]{[3-[4-(3,4-Dimethoxy-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0064]({3-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0065]{[3-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0066]{Methyl-[3-(3-methyl-4-p-tolyloxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0067]({3-(4-Fluoro-phenyl)-3-[4-(4-methoxy-phenoxy)-3-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0068]{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-chloro-phenyl)-propyl]-methyl-amino}-aceticacid

[0069]({3-(4-Fluoro-phenyl)-3-[4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0070]{[3-[4-(3-Methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0071]({3-(4-Chloro-phenyl)-3-[4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0072]{[3-[4-(4-Methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0073]({3-(4-Chloro-phenyl)-3-[4-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0074]{[3-[2-Chloro-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0075]{[3-(4-Fluoro-phenyl)-3-(3-methyl-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0076]{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0077]{[3-[2-Chloro-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0078]{[3-[3-Methoxy-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0079]({3-(4-Fluoro-phenyl)-3-[3-methoxy-4-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0080]({3-(4-Fluoro-phenyl)-3-[3-methoxy-4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0081]({3-[3-Methoxy-4-(3-methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0082]({3-[3-Methoxy-4-(4-methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0083]({3-[4-(3-Methoxy-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0084]{[3-[3-Methoxy-4-(3-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0085]{[3-(3-Methoxy-4-phenoxy-phenoxy)-3-phenyl-propyl]-methyl-amino}-aceticacid

[0086]{[3-(4-Fluoro-phenyl)-3-(3-methoxy-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0087]{[3-(4-Fluoro-phenyl)-3-(2-methyl-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0088]{Methyl-[3-(2-methyl-4-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0089]({3-[4-(4-Methoxy-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0090]({3-[4-(4-Chloro-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0091]{Methyl-[3-(2-methyl-4-p-tolyloxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0092]{[3-(2-Chloro-4-phenoxy-phenoxy)-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0093]{[3-(2-Chloro-4-p-tolyloxy-phenoxy)-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0094]{[3-[2-Chloro-4-(4-chloro-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0095] {Methyl-[3-(3-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0096]{[3-(4-Fluoro-phenyl)-3-(3-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0097]{[3-(4-Fluoro-phenyl)-3-(3-p-tolyloxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0098]({3-(4-Fluoro-phenyl)-3-[3-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0099]({3-[3-(4-Chloro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0100]{[3-[3-(4-Chloro-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0101]({3-(4-Fluoro-phenyl)-3-[3-(2-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0102]{[3-(4-Fluoro-phenyl)-3-(4-methyl-3-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0103]({3-(4-Fluoro-phenyl)-3-[3-(3-methoxy-phenoxy)-4-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0104]({3-(4-Fluoro-phenyl)-3-[3-(4-methoxy-phenoxy)-4-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0105]{[3-[3-(Benzo[1,3]dioxol-5-yloxy)-4-methyl-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0106](Methyl-{3-phenyl-3-[4-(pyridin-4-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0107]({3-(4-Fluoro-phenyl)-3-[4-(pyridin-4-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0108](Methyl-{3-phenyl-3-[4-(pyridin-3-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0109]({3-(4-Fluoro-phenyl)-3-[4-(pyridin-3-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0110](Methyl-{3-phenyl-3-[4-(pyridin-2-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0111]({3-(4-Fluoro-phenyl)-3-[4-(pyridin-2-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0112] This invention also relates to a method of treating a disorder orcondition selected from psychosis, schizophrenia, conduct disorder,disruptive behavior disorder, bipolar disorder, psychotic episodes ofanxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania or depression associated withbipolar disorder and mood disorders associated with schizophrenia,behavioral manifestations of mental retardation, conduct disorder andautistic disorder; movement disorders such as Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia and other drug induced and neurodegenerationbased dyskinesias; attention deficit hyperactivity disorder; cognitivedisorders such as dementias (including age related dementia, and seniledementia of the Alzheimer's type) and memory disorders in a mammal,including a human, comprising administering to a mammal in need of suchtreatment an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch condition or disorder.

[0113] This invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from psychosis, schizophrenia,conduct disorder, disruptive behavior disorder, bipolar disorder,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders such as acute mania ordepression associated with bipolar disorder and mood disordersassociated with schizophrenia, behavioral manifestations of mentalretardation, conduct disorder and autistic disorder; movement disorderssuch as Tourette's syndrome, akinetic-rigid syndrome, movement disordersassociated with Parkinson's disease, tardive dyskinesia and other druginduced and neurodegeneration based dyskinesias; attention deficithyperactivity disorder; cognitive disorders such as dementias (includingage related dementia and senile dementia of the Alzheimer's type) andmemory disorders in a mammal, including a human, comprising a compoundof the formula I, or a pharmaceutically acceptable salt thereof, in anamount that is effective for treating such disorder or condition.

[0114] This invention also relates to a method of treating a disorder orcondition selected from psychosis, schizophrenia, conduct disorder,disruptive behavior disorder, bipolar disorder, psychotic episodes ofanxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania or depression associated withbipolar disorder and mood disorders associated with schizophrenia,behavioral manifestations of mental retardation, conduct disorder andautistic disorder; movement disorders such as Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia and other drug induced and neurodegenerationbased dyskinesias; attention deficit hyperactivity disorder; cognitivedisorders such as dementias (including age related dementia and seniledementia of the Alzheimer's type) and memory disorders in a mammal,including a human, comprising administering to a mammal in need of suchtreatment a glycine transport-inhibiting amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof.

[0115] This invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from psychosis, schizophrenia,conduct disorder, disruptive behavior disorder, bipolar disorder,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders such as acute mania ordepression associated with bipolar disorder and mood disordersassociated with schizophrenia, behavioral manifestations of mentalretardation, conduct disorder and autistic disorder; movement disorderssuch as Tourette's syndrome, akinetic-rigid syndrome, movement disordersassociated with Parkinson's disease, tardive dyskinesia and other druginduced and neurodegeneration based dyskinesias; attention deficithyperactivity disorder; cognitive disorders such as dementias (includingage related dementia and senile dementia of the Alzheimer's type) andmemory disorders in a mammal, including a human, comprising a compoundof the formula I, or a pharmaceutically acceptable salt thereof, in aglycine transport-inhibiting amount.

[0116] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof. Examples of “alkyl”groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and the like.

[0117] The term “halo”, as used herein, means chloro, fluoro, iodo orbromo.

[0118] The term “alkoxy”, as used herein, means “alkyl-O—”, wherein“alkyl” is defined as above.

[0119] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchcondition or disorder. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0120] The compounds of formula I may have optical centers and thereforemay occur in different enantiomeric configurations. Formula I, asdepicted above, includes all enantiomers, diastereomers, and otherstereoisomers of the compounds depicted in structural formula I, as wellas racemic and other mixtures thereof. Individual isomers can beobtained by known methods, such as optical resolution, opticallyselective reaction, or chromatographic separation in the preparation ofthe final product or its intermediate.

[0121] The present invention also includes isotopically labelledcompounds, which are identical to those recited in formula I, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the present invention include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively. Compounds of the present invention, prodrugsthereof, and pharmaceutically acceptable salts of said compounds or ofsaid prodrugs which contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritium and ¹⁴C isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium can afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements and, hence,may be preferred in some circumstances. Isotopically labelled compoundsof formula I of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the Scheme and/orin the Examples and Preparations below, by substituting a readilyavailable isotopically labelled reagent for a non-isotopically labelledreagent.

DETAILED DESCRIPTION OF THE INVENTION

[0122] The compounds of the formula (I) of this invention may beprepared as described in the following reaction schemes.

[0123] Unless otherwise indicated, in the reaction schemes anddiscussion that follow, X and Y are defined as above.

[0124] Scheme I illustrates methods of preparing compounds of theformula I wherein ring A is phenyl. Methods analogous to these can beused to prepare compounds of the formula I wherein ring A is other thanphenyl. Such methods will be understood by those of skill in the art.

[0125] Referring to Scheme I, a compound of formula V is reacted with4-fluorobenzaldehyde (VI) in the presence of an alkali metal or alkalineearth metal carbonate or bicarbonate to form the corresponding ether offormula IV. This reaction is typically conducted in a reaction-inertsolvent such as dimethyl formamide (DMF), methyl pyrrolidone ordimethylacetamide, at a temperature from about 100° C. to about 170° C.,preferably at about 150° C. The resulting compound of formula IV is thenoxidized to the corresponding phenolic alcohol compound of formula IIIusing a peracid, such as peracetic, trifluoroacetic, perbenzoic orm-chloroperbenzoic acid, in an inert organic solvent, such asdichloromethane. As an alternative, and especially when the X-bearingphenyl ring is a pyridyl ring, this oxidation may be carried out usinghydrogen peroxide, preferably 30% strength, and boric acid, with a smallamount of sulfuric acid, in an inert solvent such as tetrahydrofuran ordioxane, at a temperature from room temperature to the refluxtemperature of the solvent, for 1 to 24 hours.

[0126] The phenolic alcohol compound of formula III is then treated witha haloalkyl-substituted benzylic alcohol of formula VI under conditionssuited to form a haloalkylphenoxy aryl compound of formula II. Thisreaction is preferably carried out using a dialkyl azodicarboxylate inthe presence of a trialkyl or triaryl phosphine. More preferably, thedialkyl azodicarboxylate is a diethyl azodicarboxylate, diisopropylazodicarboxylate, or diisobutyl azodicarboxylate, and the phosphine istri-n-butylphospine, triphenylphospine, or tri-p-tolylphospine. Thereaction is typically performed in a dipolar ether such as THF, at atemperature from about 50° C. to about 120° C., preferably at about thereflux temperature of THF.

[0127] The compound of formula II is treated with an aminoacetic estersuch as N-methyl glycine ethyl ester (sarcosine ethyl ester) in thepresence of an organic base such as diisopropylethylamine ordiethylamine. This reaction is typically conducted in a reaction-inertsolvent such as N-methylpyrrolidinone or dimethyl formamide, at atemperature from about room temperature to about 150° C., preferably atabout 90° C. Then, the resulting ester is hydrolyzed using an alkalimetal carbonate or bicarbonate or an alkali metal hydroxide, preferablyan alkali metal hydroxide, such as lithium hydroxide, in water, amixture of water, an alcohol containing one to four carbons and/or anethereal solvent such as tetrahydrofuran to form the correspondingcarboxylic acid of formula I. The hydrolysis reaction can be carried outin situ or after isolating the ester from the alkylation reaction. Ineither case, the hydrolysis is carried out using the same or similarsolvent as that used in the alkylation reaction and is carried out underthe same or similar conditions.

[0128] Scheme II illustrates methods of preparing compounds of theformula I wherein ring A is in the 3- (or meta) position. Methodsanalogous to these can be used to prepare compounds of the formula Iwherein ring A is other than phenyl. Such methods will be understood bythose of skill in the art.

[0129] Referring to Scheme II, 3-benzyloxyphenol is reacted with an arylboronic acid using cupric acetate, cupric trifluoroacetate, or a relatedcopper salt, a base such as pyridine, triethylamine, or an organic aminebase, and dimethylsulfoxide or methylene chloride as solvent under anoxygen atmosphere at room temperature to 100° C. for 12 to 100 hours toafford intermediate VII. Compound VII is then reacted to intermediateVIII by treating it with ammonium formate and palladium in ethanol or ahigher alcohol. The reaction may also be carried out using palladiumunder a hydrogen atmosphere, or using boron tribromide in methylenechloride at −78° C. to room temperature for 1 to 24 hours. IntermediateVIII is then processed to compound IX as detailed above in Scheme 1 forcompound II. Compound IX is then reacted as detailed in Scheme 1 toproduce the compound of formula I.

[0130] The compounds of formula I and the intermediates shown in theabove reaction schemes can be isolated and purified by conventionalprocedures, such as recrystallization or chromatographic separation.

[0131] In so far as the compounds of formula (I) of this invention cancontain basic substituents, they are capable of forming a wide varietyof different salts with various inorganic and organic acids. Althoughsuch salts must be pharmaceutically acceptable for administration toanimals, it is often desirable in practice to initially isolate the basecompound from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert to the free base compound by treatment withan alkaline reagent and thereafter convert the free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained.

[0132] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate,phosphate or acid phosphate, acetate, lactate, citrate or acid citrate,tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, ptoluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate))salts.

[0133] All compounds of the invention have an acidic group and arecapable of forming base salts with various pharmaceutically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and, particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques.

[0134] The chemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic derivatives.These particular non-toxic base salts include those derived form suchpharmaceutically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating theaforementioned acidic compounds with an aqueous solution containing thedesired pharmaceutically acceptable cation, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanoicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum production of yields of the desired final product.

[0135] The compounds of the present invention exhibit significantglycine transport inhibiting activity and therefore are of value in thetreatment of a wide variety of clinical conditions that arecharacterized by the deficit of glutamateric neurotransmission inmammalian subjects, especially humans. Such conditions include thepositive and negative symptoms of schizophrenia and other psychoses, andcognitive deficits.

[0136] The compounds of the formula (I) of this invention can beadministered via either the oral, parenteral (such as subcutaneous,intraveneous, intramuscular, intrasternal and infusion techniques),rectal, intranasal or topical routes to mammals. In general, thesecompounds are most desirably administered to humans in doses rangingfrom about 1 mg to about 2000 mg per day, although variations willnecessarily occur depending upon the weight and condition of the subjectbeing treated and the particular route of administration chosen.However, a dosage level that is in the range of from about 0.1 mg toabout 20 mg per kg of body weight per day is most desirably employed.Nevertheless, variations may still occur depending upon the species ofanimal being treated and its individual response to said medicament, aswell as on the type of pharmaceutical formulation chosen and the timeperiod and interval at which such administration is carried out. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effects provided that suchhigher dose levels are first divided into several small doses foradministration throughout the day.

[0137] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the above routes previously indicated, and suchadministration can be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically effective compounds of this inventionare present in such dosage forms at concentration levels ranging about5.0% to about 70% by weight.

[0138] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0139] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH>8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

[0140] The compounds of the present invention were assayed for theiractivity in inhibiting glycine reuptake in synaptosomes by firstpreparing synaptosomes and then measuring neurotransmitter reuptakeactivity as follows:

[0141] Male Sprague Dawley rats were decapitated and the brains removed.The whole brains were dissected out and placed in ice cold sucrosebuffer; 1 gram in 20 mis (320 mM sucrose containing 1 mg/ml glucose, 0.1mM EDTA and brought up to pH 7.4 with Tris base). The tissue washomogenized in a glass homogenizing tube with a teflon pestle at 350RPMS using a Potters homogenizer. The homogenate was centrifuged at1000×g for 10 min at 4° C. The resulting supernatant was recentrifugedat 17,000×g for 20 min at 4° C. The final pellet was resuspended in anappropriate volume of sucrose buffer containing 5 mM alanine, to yieldless than 10% uptake.

[0142] The uptake assays were conducted in 96 well matrix plates. Eachwell contained 25 μL of solvent, inhibitor or 10 mM glycine fornonspecific uptake, 200 μL of [³H]-glycine (40 nM final), made up inmodified Krebs containing 5 mM alanine and glucose (1 mg/ml) and 25 μLof synaptosomes. The plates were then incubated at room temperature forthe 15 min. The incubation was terminated by filtration through GF/Bfilters, using a 96 well Brandel Cell Harvester. The filters were washedwith modified Krebs buffer and either counted in a liquid scintillationcounter or in a LKB Beta Plate counter. Compounds of the inventionanalyzed by this assay have been found to have significant activity ininhibiting glycine reuptake in synaptosomes, having IC₅₀ values morepotent than 10 μM.

[0143] The present invention is illustrated by the following examples.However, it should be understood that the invention is not limited tothe specific details of these examples. Melting points were taken with aBuchi micro melting point apparatus and uncorrected. Infrared Rayabsorption spectra (IR) were measured by a Shimazu infrared spectrometer(IR-470). ¹H and ¹³C nuclear magnetic resonance spectra (NMR) weremeasured in CDCl₃ by a Varian NMR spectrometer (Unity, 400 MHz for ¹H,100 MHz for ¹³C) unless otherwise indicated and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(δ). The peak shapes are denoted as follows: s, singlet; d, doublet; t,triplet; m, multiplet; br, broad.

EXAMPLE 1(Methyl-{3-phenyl-3-[4-(3trifluoromethylphenoxy)phenoxy]propyl}amino)aceticacid A. [4-(3-Trifluoromethyl)phenoxy]benzaldehyde

[0144] As described in Synthesis, 63, (1991): To a 125 ml round-bottomedflask equipped with condenser and nitrogen gas inlet were added 1.07 ml(10 mmol) 4-fluorobenzaldehye, 1.22 ml (10 mmol)3-trifluoromethylphenol, 1.66 g (12 mmol) potassium carbonate, and 10 mldry N-methylpyrrolidin-2-one. The reaction was heated at 150° C. for 14hours (h), and the black mixture cooled to room temperature, poured intowater, and extracted into ethyl acetate. The organic layer was washedwith several portions of water, brine, then dried over sodium sulfateand evaporated. The residue was filtered through silica gel withhexane/ethyl acetate to afford a yellow oil, 2.46 g (92.5%).

[0145]¹H-NMR (δ, CDCl₃): 7.05 (m, 2H), 7.23 (m, 1H), 7.305 (m, 1H),7.4-7.6 (m, 2H), 7.84 (m, 2H), 9.92 (s, 1H).

[0146]¹³C-NMR (δ, CDCl₃): 117.24, 118.36, 121.54, 121.62, 123.52,130.97, 132.28, 155.89, 162.26, 190.85 (signals for the CF₃ and adjacentcarbon not visible in this scan).

B. [4-(3-Trifluoromethyl)phenoxy]phenol

[0147] As described in Synthesis, page 63, 1991: To a 125 mLround-bottomed flask equipped with condenser and a nitrogen inlet wereadded 2.46 g (9.25 mmol) [4-(3-trifluoromethyl)phenoxy]benzaldehyde,2.39 g (11.1 mmol) m-chloroperbenzoic acid (80%), and 25 ml drymethylene chloride. The reaction was stirred at room temperature for 8hr, filtered, and the filtrate washed with aqueous sodium bisulfitesolution, aqueous sodium bicarbonate solution, dried over sodiumsulfate, and evaporated. The residue was taken up in 50 ml methanol,treated with 3 drops concentrated hydrochloric acid, and stirred at roomtemperature for 14 h. The residue after evaporation was filtered throughsilica gel using ethyl acetate and hexane to afford 2.48 g (100%) of anoil.

[0148]¹H-NMR (δ, CDCl₃): 6.84 (m, 2H), 6.90 (m, 2H), 7.05 (m, 1H), 7.13(m, 1H), 7.24 (m, 1H), 7.35 (m, 1H).

[0149]¹³C-NMR (δ, CDCl₃): 114.17, 116.80, 119.03, 120.56, 121.61,130.33, 148.96, 153.12, 159.23 (signals for the CF₃and adjacent carbonnot visible in this scan).

C. 3-Phenyl-3-[4-(3-trifluoromethylphenoxy)phenoxy]-1-chloropropane

[0150] To a 125 mL round-bottomed flask equipped with a nitrogen inletwere added 0.50 g (2.93 mmol) 3-chloro-1-phenylpropanol, 745 mg (2.93mmol) [4-(3-trifluoromethyl)phenoxy]phenol, 0.64 ml (3.22 mmol)diisopropylazodicarboxylate, 0.85 g (3.22 mmol) triphenylphosphine, and15 ml dry tetrahydrofuran. The reaction was refluxed for 14 h, cooled,and evaporated. The residue was chromatographed on silica gel usingethyl acetate in hexane as eluant to afford 486 mg (41%) of an oil.

[0151]¹H-NMR (δ, CDCl₃): 2.21 and 2.47 (multiplets, 2H), 3.61 and 3.82(multiplets, 2H), 5.33 (m, 1H), 6.85 (m, 4H), 7.04 (m, 1H), 7.26 (m,1H), 7.2-7.4 (m, 7H).

[0152]¹³C-NMR (δ, CDCl₃): 41.53, 41.58, 77.70, 117.55, 119.19, 119.22,119.26, 120.78, 121.12, 126.17, 128.24, 129.05, 130.35, 140.89, 149.63,158.90 (signals for the CF₃ and adjacent carbon not visible in thisscan).

D.(Methyl-{3-phenyl-3-[4-(3-trifluoromethylphenoxy)phenoxy]propyl}amino)aceticacid ethyl ester

[0153] To a 125 mL round-bottomed flask equipped with condenser andnitrogen inlet were added 486 mg (1.20 mmol)3-phenyl-3-[4-(3-trifluoromethyl-phenoxy)-phenoxy]-1-chloropropane, 184mg (1.20 mmol) sarcosine ethyl ester hydrochloride, 0.416 mL (2.40 mmol)diisopropylethylamine, and 6 mL dry N-methylpyrrolidinone. The reactionwas heated at 90-95° C. for 60 h, cooled, and poured into water. Afterextracting with ethyl acetate, the organic layer was washed with water(3 times) and brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using methylenechloride/methanol as eluant to afford 250 mg (43%) of an oil.

[0154]¹H-NMR (δ, CDCl₃): 1.22 (t, J=7, 3H), 1.99 and 2.18 (multiplets,2H), 2.38 (s, 3H), 2.68 (m, 2H), 3.24 (s, 2H), 4.12 (q, J=7, 2H), 5.18(m, 1H), 6.83 (s, 4H), 7.02 (m, 1H), 7.10 (m, 1H), 7.2-7.4 (m, 7H).

[0155]¹³C-NMR (δ, CDCl₃): 14.46, 36.88, 42.51, 53.46, 58.82, 60.69,78.99, 114.44, 117.48, 119.11, 120.69, 121.09, 126.20, 127.87, 128.86,130.30, 141.91, 149.28, 155.25, 155.27, 158.99 (signals for the CF₃ andadjacent carbon not visible in this scan).

[0156] MS (%): 488 (parent+1, 100).

E.(Methyl-{3-phenyl-3-[4-(3-trifluoromethylphenoxy)phenoxy]propyl}amino)aceticacid

[0157] To a 125 mL round-bottomed flask equipped with condenser andnitrogen inlet were added 250 mg (0.514 mmol){[3-(4-(3-trifluoromethyl)phenoxy)phenoxy)-3-phenylpropyl]methylamino}-aceticacid ethyl ester, 6 ml tetrahydrofuran, a solution of 100 mg lithiumhydroxide hydrate in 10 ml water, and enough methanol to afford asolution. The reaction was stirred at room temperature for 1 h,evaporated, and taken up in water to pH 1 with 6 N hydrochloric acid.The aqueous layer was extracted with several portions of methylenechloride, and the organic layer washed with brine, dried over sodiumsulfate, and evaporated to a foam, 225 mg (38%).

[0158]¹³C-NMR (δ, CDCl₃): 33.32, 41.76, 54.53, 56.62, 78.02, 114.45,117.61, 119.28, 120.77, 121.11, 123.92 (q, J=269, CF₃), 126.14, 128.46,129.16, 130.40, 132.17 (q, J=29), 140.10, 149.76, 154.26, 158.71,167.44.

[0159] MS (%): 460 (parent+1, 100).

[0160] Anal. Calc'd. for C₂₅H₂₄NO₄F₃.HCl: C, 60.55; H, 5.08; N, 2.82.Found: C, 60.65; H, 5.64; N, 2.60.

EXAMPLE 2 {Methyl-[3-phenyl-3-(4-p-tolyloxyphenoxy)propyl]amino}aceticacid

[0161] Prepared as in Example 1, in 9.5% yield, as a foam.

[0162]¹³C-NMR (δ, CDCl₃): 33.36, 41.73, 54.45, 56.67, 78.02, 117.32,117.98, 118.29, 120.10, 126.17, 128.36, 129.01, 129.11, 130.33, 132.45,132.64, 140.34, 151.52, 153.38, 155.75, 167.66.

[0163] MS (%): 406 (parent+1, 100).

[0164] Anal. Calc'd. for C₂₅H₂₇NO₄HCl.1/4H₂O: C, 67.26; H, 6.43; N,3.14. Found: C, 67.04; H, 7.00; N, 2.96.

EXAMPLE 3({3-[4-(4-Methoxyphenoxy)phenoxy]-3-phenylproyl}methylamino)-acetic acid

[0165] Prepared as in Example 1, in 43% yield, as a foam.

[0166]¹³C-NMR (δ, CDCl₃): 33.38, 41.54, 41.93, 54.55, 56.39, 77.96,114.96, 117.33, 119.30, 120.02, 126.18, 128.35, 129.10, 140.32, 151.19,152.34, 153.05, 155.65, 167.18.

[0167] MS (%): 422 (parent+1, 100).

[0168] Anal. Calc'd. for C₂₅H₂₇NO₅.HCl.H₂O: C, 63.09; H, 6.35; N, 2.94.Found: C, 62.84; H, 6.43; N, 3.34.

EXAMPLE 4({3-[4-(4-Chlorophenoxy)phenoxy]-3-phenylpropyl}methylamino)acetic acid

[0169] Prepared as in Example 1, in 37% yield, as a foam.

[0170]¹³C-NMR (δ, CDCl₃): 33.35, 41.86, 53.69, 54.46, 56.60, 78.00,117.45, 119.20, 120.69, 126.13, 127.73, 128.45, 129.15, 129.76, 140.17,150.51, 153.89, 156.88, 167.56.

[0171] MS (%): 426 (parent+1, 100).

[0172] Anal. Calc'd. for C₂₄H₂₄NO₄Cl.HCl.H₂O: C, 60.01; H, 5.67; N,2.92. Found: C, 60.16; H, 5.36; N, 2.69.

EXAMPLE 5(Methyl-{3-[4-(naphthalen-2-yloxy)phenoxy]-3-phenylpropyl}amino)aceticacid

[0173] Prepared as in Example 1, in 23% yield, as a foam.

[0174]¹³C-NMR (δ, CDCl₃): 33.39, 41.60, 42.01, 54.66, 56.47, 78.03,112.87, 117.50, 119.59, 120.86, 124.68, 126.20, 126.71, 127.23, 127.88,128.43, 129.16, 129.99, 130.02, 134.45, 140.23, 150.80, 153.82, 156.09,167.06.

[0175] MS (%): 442 (parent+1, 100).

[0176] Anal. Calc'd. for C₂₈H₂₇NO₄.HCl.3/2H₂O: C, 66.59; H, 6.19; N,2.77. Found: C, 66.37; H, 6.01; N, 2.82.

EXAMPLE 6({3-[4-(4-Isopropylphenoxy)phenoxy]-3-phenylpropyl}methylamino)aceticacid

[0177] Prepared as in Example 1, in 24% yield, as a foam.

[0178]¹³C-NMR (δ, CDCl₃): 24.35, 33.04, 33.59, 41.63, 42.05, 54.70,55.75, 56.36, 78.02, 117.33, 118.13, 120.25, 126.18, 127.66, 128.37,129.12, 140.26, 143.51, 151.45, 153.38, 155.95, 166.82.

[0179] MS (%): 434 (parent+1, 100).

[0180] Anal. Calc'd. for C₂₇H₃₁NO₄.HCl.3/4H₂O: C, 67.07; H, 6.98; N,2.90. Found: C, 67.32; H, 7.22; N, 2.73.

EXAMPLE 7({3-[4-(4-t-Butylphenoxy)phenoxy]-3-phenylpropyl}methylamino)acetic acid

[0181] Prepared as in Example 1, in 39% yield, as a foam.

[0182]¹³C-NMR (δ, CDCl₃): 31.73, 33.34, 34.46, 41.81, 54.57, 56.56,78.06, 117.44, 117.74, 120.37, 125.77, 126.27, 126.67, 128.38, 129.15,140.40, 145.76, 151.35, 153.49, 155.73, 167.50.

[0183] MS (%): 448 (parent+1, 100).

[0184] Anal. Calc'd. for C₂₈H₃₃NO₄.HCl.2H₂O: C, 64.67; H, 7.36; N, 2.69.Found: C, 64.89; H, 7.18; N, 2.70.

EXAMPLE 8(Methyl-{3-phenyl-3-[4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)phenoxy]propyl}amino)aceticacid

[0185] Prepared as in Example 1, in 29% yield, as a foam.

[0186]¹³C-NMR (δ, CDCl₃): 23.21, 23.48, 28.90, 29.71, 33.04, 33.39,41.68, 42.10, 53.71, 54.65, 55.81, 56.44, 78.03, 115.85, 117.33, 118.56,120.12, 126.22, 128.35, 129.11, 130.31, 131.80, 138.75, 140.29, 151.53,153.27, 155.56, 167.10.

[0187] MS (%): 446 (parent+1, 100).

[0188] Anal. Calc'd. for C₂₈H₃₁NO₄.HCl.3/2H₂O: C, 66.07; H, 6.93; N,2.75. Found: C, 66.36; H, 7.10; N, 2.80.

EXAMPLE 9(Methyl-{3-phenyl-3-[4-(4-trifluoromethylphenoxy)phenoxy]proryl}amino)aceticacid

[0189] Prepared as in Example 1, in 41.5% yield, as a foam.

[0190]¹³C-NMR (δ, CDCl₃): 33.39, 41.67, 53.71, 54.32, 56.62, 78.10,117.18, 117.54, 121.49, 123.06, 124.47 (q, J=33), 124.59 (q, J=270,CF₃), 127.17, 127.21, 128.46, 129.15, 140.13, 149.36, 154.44, 161.25,167.86.

[0191] MS (%): 460 (parent+1, 100).

[0192] Anal. Calc'd. for C₂₅H₂₄NO₄F₃.HCl.H₂O: C, 58.43; H, 5.30; N,2.73. Found: C, 58.80; H, 5.22; N, 2.85.

EXAMPLE 10({3-(4-Fluoro-phenyl)-3-[4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0193] Prepared as in Example 1, in 93% yield, as a solid, mp 60-61° C.

[0194]¹³C-NMR (δ, CDCl₃): 22.84, 22.99, 23.47, 25.82, 29.73, 33.89,41.58, 53.74, 58.74, 68.16, 77.65, 115.28, 115.99 (d, J=22), 117.19,119.25, 124.34, 126.05, 127.85 (d, J=8), 128.73, 136.45, 136.48, 139.52,151.86, 152.94, 155.27, 162.50 (d, J=246), 168.80.

[0195] MS (%): 464 (parent+1, 100).

[0196] HRMS Calc'd. for C₂₈H₃₁NO₄F: 464.2238. Found: 464.2218.

EXAMPLE 11{[3-[4-(2,4-Dimethyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0197] Prepared as in Example 1, in 98% yield, as a foam.

[0198]¹³C-NMR (δ, CDCl₃): 16.29, 20.87, 33.51, 41.57, 53.99, 58.39,77.6, 116.00 (d, J=22), 117.24, 118.43, 119.16, 127.69, 127.91 (d, J=7),129.41, 132.20, 133.31, 133.33, 136.25, 136.28, 152.51, 152.54, 152.85,162.50 (d, J=246), 168.65.

[0199] MS (%): 438 (parent+1, 100).

[0200] HRMS Calc'd. for C₂₆H₂₉NO₄F: 438.2081. Found: 438.2111.

EXAMPLE 12({3-(4-Fluoro-phenyl)-3-[4-(2,4,6-trimethyl-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0201] Prepared as in Example 1, in 100% yield, as a foam.

[0202]¹³C-NMR (δ, CDCl₃): 14.38, 16.43, 20.93, 21.07, 21.24, 33.38,41.72, 54.36, 57.76, 60.63, 115.35, 115.97 (d, J=21), 117.25, 127.89 (d,J=8), 129.73, 131.12, 134.51, 136.23, 136.26, 149.22, 151.59, 152.83,162.50 (d, J=246), 168.53, 171.46, 175.44.

[0203] MS (%): 452 (parent+1, 100).

[0204] HRMS Calc'd. for C₂₉H₃₀NO₄F: 452.2238. Found: 452.2255.

EXAMPLE 13(Methyl-{3-phenyl-3-[4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0205] Prepared as in Example 1, in 100% yield, as a foam.

[0206]¹³C-NMR (δ, CDCl₃): 22.87, 23.00, 23.49, 29.75, 33.36, 41.69,54.36, 56.96, 60.66, 78.12, 115.16, 117.34, 119.36, 124.26, 126.07,126.21, 128.30, 128.60, 129.08, 139.45, 140.45, 151.71, 153.08, 155.37,168.25.

[0207] MS (%): 446 (parent+1, 100).

[0208] Anal. Calc'd. for C₂₈H₃₁NO₄.HCl.H₂O: C, 67.26; H, 6.85; N, 2.80.Found: C, 67.45; H, 6.89; N, 2.69.

EXAMPLE 14({3-[4-(2,4-Dimethyl-phenoxy)-phenoxy]-3-phenyl-proyyl}-methyl-amino)-aceticacid

[0209] Prepared as in Example 1, in 100% yield, as a solid, mp 53-55° C.

[0210]¹³C-NMR (δ, CDCl₃): 16.32, 20.87, 33.77, 41.49, 53.71, 58.62,60.59, 78.26, 117.13, 118.46, 119.11, 126.07, 127.67, 128.22, 129.04,129.37, 132.17, 133.15, 140.73, 152.30, 152.92, 153.00, 168.82.

[0211] MS (%): 420 (parent+1, 100).

[0212] Anal. Calc'd. for C₂₆H₂₉NO₄.HCl.H₂O: C, 65.88; H, 6.80; N, 2.96.Found: C, 66.08; H, 6.96; N, 2.93.

EXAMPLE 15{[3-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0213] Prepared as in Example 1, in 85% yield, as a foam.

[0214]¹³C-NMR (δ, CDCl₃): 21.70, 26.33, 27.10, 33.34, 34.85, 41.87,44.02, 54.31, 59.00, 77.66, 116.06 (d, J=21), 117.27, 118.13, 119.54,120.27, 127.92 (d, J=8), 128.06, 136.27, 136.30, 142.90, 151.61, 153.25,155.94, 155.97, 162.58 (d, J=246), 169.80, 176.69.

[0215] MS (%): 492 (parent+1, 100).

EXAMPLE 16{[3-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0216] Prepared as in Example 1, in 88% yield, as a foam.

[0217]¹³C-NMR (δ, CDCl₃): 25.62, 34.90, 41.62, 45.45, 53.75, 58.93,60.60, 116.01 (d, J=21), 117.25, 118.15, 120.22, 127.89 (d, J=9),128.36, 136.49, 141.17, 151.58, 153.34, 155.92, 162.52, (d, J=245),168.96, 171.36.

[0218] MS (%): 478 (parent+1, 100).

EXAMPLE 17({3-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0219] Prepared as in Example 1, in 98.5% yield, as a foam.

[0220]¹³C-NMR (δ, CDCl₃): 26.32, 27.09, 29.65, 33.66, 34.82, 41.71,43.99, 53.99, 59.10, 78.18, 117.14, 118.05, 120.29, 126.04, 128.00,128.30, 129.09, 140.53, 142.77, 151.37, 153.50, 156.02, 168.57.

[0221] MS (%): 474 (parent+1, 100).

[0222] HRMS Calc'd. for C₃₀H₃₆NO₄: 474.2645. Found: 474.2642.

EXAMPLE 18({3-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0223] Prepared as in Example 1, in 93% yield, as a yellowish solid.

[0224]¹³C-NMR (δ, CDCl₃): 14.40, 25.60, 33.71, 34.88, 41.69, 45.44,53.89, 60.59, 78.22, 117.14, 118.08, 120.22, 126.04, 128.30, 129.07,140.60, 141.05, 151.38, 153.53, 155.99, 168.66.

[0225] MS (%): 460 (parent+1, 100).

[0226] HRMS Calc'd. for C₂₉H₃₄NO₄: 460.2488. Found: 460.2513.

EXAMPLE 19{[3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0227] Prepared as in Example 1, in 91% yield, as a foam.

[0228]¹³C-NMR (δ, CDCl₃): 14.38, 21.39, 33.41, 41.60, 54.01, 58.53,60.60, 64.41, 64.60, 77.63, 111.94, 112.64, 115.98 (d, J=21), 117.21,119.11, 120.45, 127.93 (d, J=8), 135.62, 136.21, 136.24, 145.06, 146.00,151.62, 153.07, 162.49 (d, J=246), 168.79, 171.41, 174.46.

[0229] MS (%): 468 (parent+1, 100).

[0230] HRMS Calc'd. for C₂₆H₂₇FNO₆: C, 468.1822. Found: 468.1795.

EXAMPLE 20({3-[4-(2,3-Dihydro-benzo[4,1]dioxin-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0231] Prepared as in Example 1, in 61% yield, as a foam.

[0232]¹³C-NMR (δ, CDCl₃): 14.40, 29.63, 33.73, 41.79, 54.00, 59.06,64.44, 64.64, 72.80, 78.21, 111.86, 112.51, 117.05, 119.20, 120.42,126.03, 128.29, 129.07, 135.56, 140.50, 145.03, 146.19, 151.40, 153.39,168.40, 171.37.

[0233] MS (%): 450 (parent+1, 100).

[0234] HRMS Calc'd. for C₂₆H₂₇NO₆: C, 450.1916. Found: 450.1911.

EXAMPLE 21{[3-[4-(2,3-Dihydro-benzofuran-7-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0235] Prepared as in Example 1, in 26% yield, as a foam.

[0236]¹³C-NMR (δ, CDCl₃): 30.31, 33.91, 41.77, 53.92, 72.10, 112.50,115.99 (d, J=22), 117.09, 118.70, 118.89, 120.27, 121.23, 127.83 (d,J=8), 129.71, 136.41, 140.86, 150.51, 151.59, 153.00, 162.55 (d, J=245).

[0237] MS (%): 452 (parent+1, 100).

[0238] HRMS Calc'd. for C₂₆H₂₇FNO₅: C, 452.1874. Found: 452.1879.

EXAMPLE 22({3-[4-(2,3-Dihydro-benzofuran-7-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0239] Prepared as in Example 1, in 21% yield, as a foam.

[0240]¹³C-NMR (δ, CDCl₃): 30.32, 33.72, 41.80, 54.02, 59.25, 72.08,78.15, 117.02, 118.73, 118.82, 120.17, 121.19, 126.03, 128.24, 129.05,129.66, 140.57, 140.98, 150.47, 150.48, 151.43, 153.22, 168.36, 171.36.

[0241] MS (%): 434 (parent+1, 100).

[0242] Anal. Calc'd. for C₂₆H₂₈NO₅: C, 434.1968. Found: 434.1950.

EXAMPLE 23{[3-[4-(Benzofuran-4-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0243] Prepared as in Example 1, in 100% yield, as a foam.

[0244]¹³C-NMR (δ, CDCl₃): 33.62, 41.58, 53.87, 58.96, 104.22, 104.26,106.71, 110.57, 116.03 (d, J=22), 117.36, 119.30, 120.36, 124.98, 127.93(d, J=24), 136.24, 136.27, 144.34, 151.11, 151.34, 153.56, 156.84,162.52 (d, J=245), 168.87.

[0245] MS (%): 450 (parent+1, 100).

[0246] Anal. Calc'd. for C₂₆H₂₄FNO₅.5/4H₂O: C, 66.11; H, 5.66; N, 2.97.Found: C, 66.26; H, 5.45; N, 2.64.

EXAMPLE 24({3-[4-(2,3-Dihydro-benzofuran-4-yloxy)-phenoxy]-3-phenyl-proyl}-methyl-amino)-aceticacid

[0247] Prepared as in Example 1, in 91% yield, as an amorphous solid.

[0248]¹³C-NMR (δ, CDCl₃): 27.62, 33.77, 41.49, 53.69, 58.59, 71.74,78.30, 104.55, 104.58, 109.91, 109.94, 116.71, 117.18, 120.03, 126.07,128.28, 129.06, 129.17, 140.56, 150.69, 153.66, 154.60, 162.21, 168.80,171.32.

[0249] MS (%): 434 (parent+1, 100).

[0250] Anal. Calc'd. for C₂₆H₂₇NO₅.5/4H₂O: C, 68.48; H, 6.52; N, 3.07.Found: C, 68.18; H, 6.50; N, 2.86.

EXAMPLE 25{[3-[4-(2,3-Dihydro-benzofuran-4-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0251] Prepared as in Example 1, in 96% yield, as a foam.

[0252]¹³C-NMR (δ, CDCl₃): 27.60, 29.65, 33.87, 41.49, 53.61, 58.68,71.72, 104.61, 109.91, 115.97 (d, J=21), 116.76, 117.26, 120.02, 120.34,127.90 (d, J=25), 129.19, 136.41, 150.83, 153.44, 154.51, 161.25, 162.47(d, J=245), 169.04, 171.31.

[0253] MS (%): 452 (parent+1, 100).

[0254] Anal. Calc'd. for C₂₆H₂₆FNO₅.3/2H₂O: C, 65.26; H, 6.11; N, 2.93.Found: C, 65.07; H, 6.21; N, 2.75.

EXAMPLE 26{[3-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0255] Prepared as in Example 1, in 68% yield, as a foam.

[0256]¹³C-NMR (δ, CDCl₃): 33.91, 41.81, 53.96, 58.96, 116.16 (d, J=22),117.28, 117.77, 121.50, 121.76, 124.47, 127.85, 133.24 (q, J=34),135.96, 148.75, 154.79, 159.51, 162.63 (d, J=246), 168.64.

[0257] MS (%): 546 (parent+1, 100).

[0258] HRMS Calc'd. for C₂₆H₂₂F₇NO₄: 546.1516. Found: C, 546.1525.

EXAMPLE 27({3-(4-Fluoro-phenyl)-3-[4-(4-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-methylamino)-aceticacid

[0259] Prepared as in Example 1, in 95% yield, as a foam.

[0260]¹³C-NMR (δ, CDCl₃): 33.71, 41.63, 53.92, 59.01, 116.08 (d, J=22),117.38, 118.72, 120.67 (q, J=256), 120.83, 122.70, 127.84 (d, J=8),136.14, 144.21, 150.55, 153.84, 156.76, 162.55 (d, J=246), 168.75.

[0261] MS (%): 494 (parent+1, 100).

[0262] HRMS Calc'd. for C₂₅H₂₃F₄NO₅: 494.1591. Found: 494.1591.

EXAMPLE 28(Methyl-{3-phenyl-3-[4-(4-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0263] Prepared as in Example 1, in 100% yield, as a foam.

[0264]¹³C-NMR (δ, CDCl₃): 33.70, 41.63, 53.88, 58.77, 60.59, 78.16,78.22, 117.31, 118.64, 120.68 (q, J=256), 120.84, 122.67, 126.01,128.37, 129.12, 140.38, 144.14, 150.34, 154.13, 156.89, 168.66, 174.31.

[0265] MS (%): 476 (parent+1, 100).

[0266] HRMS Calc'd. for C₂₅H₂₄F₃NO₅: 476.1685. Found: 476.1683.

EXAMPLE 29{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0267] Prepared as in Example 1, in 90% yield, as a foam.

[0268]¹³C-NMR (δ, CDCl₃): 33.63, 41.51, 53.82, 58.90, 77.63, 101.47,101.53, 101.62, 108.35, 111.03, 111.07, 112.50, 116.00 (d, J=22),117.24, 119.54, 127.87 (d, J=8), 136.29, 143.52, 148.46, 152.09, 152.48,153.11, 162.48 (d, J=246), 168.75, 171.41.

[0269] MS (%): 454 (parent+1, 100).

[0270] Anal. Calc'd. for C₂₅H₂₄FNO₆.3/4H₂O: C, 64.30; H, 5.50; N, 3.00.Found: C, 64.27; H, 5.40; N, 2.83.

EXAMPLE 30({3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0271] Prepared as in Example 1, in 66% yield, as a foam.

[0272]¹³C-NMR (δ, CDCl₃): 33.73, 41.66, 53.87, 58.96, 78.19, 101.45,101.52, 101.60, 108.34, 111.01, 117.11, 119.57, 126.02, 128.29, 129.08,140.51, 143.46, 148.41, 148.45, 151.92, 152.62, 153.38, 168.43, 171.36.

[0273] MS (%): 436 (parent+1, 100).

[0274] HRMS Calc'd. for C₂₅H₂₆NO₆: 436.1760. Found: 436.1730.

EXAMPLE 31({3-[4-(3-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0275] Prepared as in Example 1, in 84% yield, as a foam.

[0276]¹³C-NMR (δ, CDCl₃): 33.77, 41.53, 53.71, 55.48, 58.73, 78.20,104.08, 108.32, 110.10, 117.19, 120.83, 126.05, 128.28, 129.08, 130.21,140.60, 150.50, 153.93, 159.56, 161.04, 168.87.

[0277] MS (%): 422 (parent+1, 100).

[0278] HRMS Calc'd. for C₂₅H₂₈NO₅: 422.1968. Found: 422.1961.

EXAMPLE 32({3-(4-Fluoro-phenyl)-3-[4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0279] Prepared as in Example 1, in 100% yield, as a foam.

[0280]¹³C-NMR (δ, CDCl₃): 33.80, 41.58, 53.73, 55.47, 58.81, 77.65,104.17, 108.32, 110.15, 116.00 (d, J=22), 117.25, 120.83, 127.85 (d,J=8), 130.23, 136.34, 150.69, 153.67, 159.47, 161.04, 162.55 (d, J=245),168.85.

[0281] MS (%): 440 (parent+1, 100).

[0282] HRMS Calc'd. for C₂₅H₂₇FNO₅: 440.1874. Found: 440.1883.

EXAMPLE 33(Methyl-{3-phenyl-3-[4-(3-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-amino)-aceticacid

[0283] Prepared as in Example 1, in 84% yield, as a foam.

[0284]¹³C-NMR (δ, CDCl₃): 33.69, 41.49, 53.72, 58.61, 60.52, 78.26,110.51, 114.60, 115.65, 117.39, 119.26, 120.53 (q, 257), 121.14, 121.81,126.04, 128.31, 129.07, 130.52, 140.47, 149.62, 150.20, 154.43, 159.61,168.99, 171.28, 174.21.

[0285] MS (%): 476 (parent+1, 100).

[0286] HRMS Calc'd. for C₂₅H₂₅F₃NO₅: 476.1685. Found: 476.1682.

EXAMPLE 34({3-(4-Fluoro-phenyl)-3-[4-(3-trifluoromethoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0287] Prepared as in Example 1, in 83% yield, as a foam.

[0288]¹³C-NMR (δ, CDCl₃): 33.77, 41.68, 53.92, 58.93, (1 signal missingin this region), 110.61, 114.76, 115.76, 116.11 (d, J=21), 117.43, 120.5(q, J=257), 121.19, 123.29, 127.84 (d, J=8), 130.57, 136.13, 149.89,150.26, 154.11, 159.52, 162.58 (d, J=245), 168.68.

[0289] MS (%): 494 (parent+1, 100).

[0290] HRMS Calc'd. for C₂₅H₂₄F₄NO₅: 496.1591. Found: 496.1600.

EXAMPLE 35({3-[4-(2-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0291] Prepared as in Example 1, in 95.5% yield, as a foam.

[0292]¹³C-NMR (δ, CDCl₃): 33.41, 41.79, 54.29, 56.11, 58.77, 78.13,112.86, 117.13, 118.95, 120.04, 121.21, 124.39, 126.08, 128.34, 129.09,140.41, 146.20, 151.13, 151.85, 153.12, 168.78, 175.05.

[0293] MS (%): 422 (parent+1, 100).

[0294] HRMS Calc'd. for C₂₅H₂₈NO₅: 422.1968. Found: 422.1961.

EXAMPLE 36({3-(4-Fluoro-phenyl)-3-[4-(2-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0295] Prepared as in Example 1, in 90% yield, as a foam.

[0296]¹³C-NMR (δ, CDCl₃): 33.83, 41.70, 53.87, 56.13, 58.95, 112.84,115.99 (d, J=22), 117.14, 118.98, 120.05, 121.21, 124.42, 127.88 (d,J=8), 136.40, 146.16, 151.14, 151.94, 153.01, 162.53 (d, J=245), 168.64.

[0297] MS (%): 440 (parent+1, 100).

[0298] HRMS Calc'd. for C₂₅H₂₇FNO₅: 440.1874. Found: 440.1863.

EXAMPLE 37({3-[4-(3,4-Dimethoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0299] Prepared as in Example 1, in 83% yield, as a foam.

[0300]¹³C-NMR (δ, CDCl₃): 33.74, 41.45, 53.63, 56.06, 56.09, 56.45,56.48, 58.49, 78.23, 103.84, 109.80, 111.88, 117.16, 119.41, 126.07,128.24, 129.04, 140.65, 145.18, 150.00, 151.63, 151.97, 153.33, 168.82.

[0301] MS (%): 452 (parent+1, 100).

[0302] HRMS Calc'd. for C₂₆H₃₀NO₆: 452.2073. Found: 452.2083.

EXAMPLE 38{[3-[4-(3,4-Dimethoxy-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0303] Prepared as in Example 1, in 85% yield, as a foam.

[0304]¹³C-NMR (δ, CDCl₃): 33.85, 41.54, 53.69, 56.08, 56.11, 56.45,56.48, 58.71, 103.92, 109.86, 111.87, 115.99 (d, J=22), 117.21, 119.38,127.88 (d, J=8), 136.44, 145.26, 150.03, 151.52, 152.19, 153.07, 162.49(d, J=246), 168.84.

[0305] MS (%): 470 (parent+1, 100).

[0306] HRMS Calc'd. for C₂₆H₂₉FNO₆: 470.1979. Found: 470.1965.

EXAMPLE 39({3-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0307] Prepared as in Example 1, in 70% yield, as a foam. ¹³C-NMR (δ,CDCl₃): 29.66, 33.56, 41.64, 53.90, 59.02, 64.32, 64.65, 78.15, 107.84,111.76, 117.15, 117.75, 119.78, 126.08, 128.27, 129.08, 139.55, 140.64,144.06, 151.73, 151.97, 153.42, 168.88, 171.39.

[0308] MS (%): 450 (parent+1, 100).

[0309] HRMS Calc'd. for C₂₆H₂₈NO₆: 450.1917. Found: 450.1905.

EXAMPLE 40{[3-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0310] Prepared as in Example 1, in 79% yield, as a foam.

[0311]¹³C-NMR (δ, CDCl₃): 29.65, 33.88, 41.54, 53.66, 58.67, 64.30,64.64, 77.70, 107.88, 111.78, 116.01 (d, J=22), 117.19, 117.77, 119.75,127.86 (d, J=8), 136.42, 136.45, 139.60, 144.07, 151.86, 151.89, 153.20,161.49 (d, J=246), 168.85.

[0312] MS (%): 468 (parent+1, 100).

[0313] HRMS Calc'd. for C₂₆H₂₇FNO₆: 468.1822. Found: 468.1829.

EXAMPLE 41{Methyl-[3-(3-methyl-4-p-tolyloxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0314] Prepared as in Example 1, in 100% yield, as a foam.

[0315] MS (%): 420 (parent+1, 100).

EXAMPLE 42({3-(4-Fluoro-phenyl)-3-[4-(4-methoxy-phenoxy)-3-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0316] Prepared as in Example 1, in 100% yield, as a foam.

[0317]¹³C-NMR (δ, CDCl₃): 16.60, 33.72, 41.71, 54.02, 55.85, 58.89,77.58, 114.02, 114.88, 116.02 (d, J=22), 118.34, 119.00, 120.09, 127.78(d, J=8), 131.07, 136.34, 149.65, 152.00, 153.29, 155.07, 162.52 (d,J=245), 168.50.

[0318] MS (%): 454 (parent+1, 100).

[0319] HRMS Calc'd. for C₂₆H₂₉FNO₅: 454.2030. Found: 454.2018.

EXAMPLE 43{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-chloro-phenyl)-propyl]-methyl-amino}-aceticacid

[0320] Prepared as in Example 1, in 70.5% yield, as a foam.

[0321]¹³C-NMR (δ, CDCl₃): 33.75, 41.58, 53.63, 58.77, 60.57, 77.63,101.53, 101.62, 108.35, 111.08, 117.12, 119.55, 127.53, 129.25, 133.95,139.19, 143.53, 148.46, 152.13, 152.49, 153.09, 168.83.

[0322] MS (%): 470 (parent+1, 100).

[0323] HRMS Calc'd. for C₂₅H₂₅ClNO₆: 470.1370. Found: 470.1370.

EXAMPLE 44{[3-[4-(3-Methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0324] Prepared as in Example 1, in 80% yield, as a foam.

[0325]¹³C-NMR (δ, CDCl₃): 33.58, 41.70, 54.03, 55.44, 55.51, 58.95,77.83, 104.09, 108.30, 110.12, 114.47, 117.31, 120.82, 127.35, 130.21,132.26, 150.50, 153.83, 159.53, 159.57, 161.02, 168.45.

[0326] MS (%): 452 (parent+1, 100).

[0327] HRMS Calc'd. for C₂₆H₃₀NO6: 452.2073. Found: 452.2061.

EXAMPLE 45({3-(4-Chloro-phenyl)-3-[4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0328] Prepared as in Example 1, in 100% yield, as a foam.

[0329]¹³C-NMR (δ, CDCl₃): 33.77, 41.62, 53.70, 55.50, 58.81, 77.62,104.20, 108.35, 110.18, 117.18, 120.85, 127.55, 129.29, 130.24, 134.00,139.13, 150.74, 153.60, 159.45, 161.05, 168.78.

[0330] MS (%): 456 (parent+1, 100).

[0331] HRMS Calc'd. for C₂₆H₂₇ClNO₅: 456.1578. Found: 456.1578.

EXAMPLE 46

[0332]{[3-[4-(4-Methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0333] Prepared as in Example 1, in 89% yield, as a foam.

[0334]¹³C-NMR (δ, CDCl₃): 33.59, 41.68, 53.99, 55.43, 55.84, 59.02,77.86, 114.44, 114.93, 117.25, 119.28, 120.01, 127.34, 132.37, 151.27,152.26, 153.14, 155.62, 159.49, 168.43.

[0335] MS (%): 452 (parent+1, 100).

[0336] HRMS Calc'd. for C₂₆H₃₀NO₆: 452.2073. Found: 452.2075.

EXAMPLE 47({3-(4-Chloro-phenyl)-3-[4-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0337] Prepared as in Example 1, in 92% yield, as a foam.

[0338]¹³C-NMR (δ, CDCl₃): 33.73, 41.70, 53.80, 55.84, 58.92, 77.58,114.96, 117.11, 119.27, 120.11, 127.53, 129.28, 133.99, 139.14, 151.13,152.55, 152.84, 155.71, 168.57.

[0339] MS (%): 456 (parent+1, 100).

[0340] HRMS Calc'd. for C₂₅H₂₇ClNO₅: 456.1578. Found: 456.1580.

EXAMPLE 48

[0341]{[3-[2-Chloro-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0342] Prepared as in Example 1, in 89% yield, as a foam.

[0343]¹³C-NMR (δ, CDCl₃): 33.65, 41.54, 53.70, 55.71, 58.83, 60.52,69.70, 78.85, 115.03, 115.93 (d, J=22), 116.82, 117.00, 119.77, 120.55,124.16, 128.01 (d, J=8), 135.87, 135.89, 148.37, 150.16, 152.84, 156.10,162.57 (d, J=245), 168.92, 171.29.

[0344] MS (%): 474 (parent+1, 100).

[0345] HRMS Calc'd. for C₂₅H₂₆ClFNO₅: 474.1485. Found: 474.1500.

EXAMPLE 49{[3-(4-Fluoro-phenyl)-3-(3-methyl-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0346] Prepared as in Example 1, in 100% yield, as a foam.

[0347]¹³C-NMR (δ, CDCl₃): 29.64, 33.91, 41.63, 53.84, 58.75, 77.59,114.19, 116.04 (d, J=22), 116.56, 118.99, 121.53, 122.11, 127.78 (d,J=8), 129.76, 131.83, 136.40, 148.28, 153.94, 158.58, 162.52 (d, J=246),168.64.

[0348] MS (%): 424 (parent+1, 100).

[0349] HRMS Calc'd. for C₂₅H₂₇FNO₄: 424.1924. Found: 424.1910.

EXAMPLE 50{[3-[4-(Benzo[1,3]dioxol-5-yloxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0350] Prepared as in Example 1, in 100% yield, as a foam.

[0351]¹³C-NMR (δ, CDCl₃): 29.62, 29.89, 33.53, 41.67, 54.01, 55.42,58.95, 77.84, 101.48, 101.60, 108.33, 110.99, 114.45, 117.29, 119.57,127.36, 132.31, 143.45, 148.44, 151.89, 152.64, 153.34, 159.50, 168.53.

[0352] MS (%): 466 (parent+1, 100).

[0353] HRMS Calc'd. for C₂₆H₂₈NO₇: 466.1866. Found: 466.1854.

EXAMPLE 51{[3-[2-Chloro-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0354] Prepared as in Example 1, in 90% yield, as a foam.

[0355]¹³C-NMR (δ, CDCl₃): 33.50, 41.62, 53.97, 55.39, 55.42, 55.81,58.99, 79.20, 114.43, 115.05, 116.93, 117.19, 119.82, 120.54, 124.19,127.52, 131.81, 148.58, 150.33, 152.70, 156.07, 159.66, 168.62.

[0356] MS (%): 486 (parent+1, 100).

EXAMPLE 52{[3-[3-Methoxy-4-(4-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0357] Prepared as in Example 1, in 93% yield, as a foam.

[0358]¹³C-NMR (δ, CDCl₃): 29.65, 33.66, 41.92, 54.18, 55.49, 55.86,56.20, 77.79, 102.52, 106.93, 114.54, 114.76, 118.34, 120.70, 127.31,132.28, 140.29, 143.47, 151.98, 152.08, 154.45, 155.16, 159.61, 168.20.

[0359] MS (%): 482 (parent+1, 100).

[0360] HRMS Calc'd. for C₂₇H₃₂NO₇: 482.2179. Found: 482.2188.

EXAMPLE 53({3-(4-Fluoro-phenyl)-3-[3-methoxy-4-(3-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0361] Prepared as in Example 1, in 93% yield, as a foam.

[0362]¹³C-NMR (δ, CDCl₃): 33.50, 41.54, 53.94, 55.47, 56.17, 58.98,60.65, 77.67, 102.62, 102.77, 107.11, 107.62, 108.62, 116.09 (d, J=22),122.43, 127.94 (d, J=8), 130.08, 136.30, 136.33, 138.57, 152.61, 155.04,159.96, 160.96, 162.55 (d, J=246), 168.93.

[0363] MS (%): 470 (parent+1, 100).

[0364] HRMS Calc'd. for C₂₆H₂₉FNO₆: 470.1979. Found: 470.1987.

EXAMPLE 54({3-(4-Fluoro-phenyl)-3-[3-methoxy-4-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0365] Prepared as in Example 1, in 100% yield, as a foam.

[0366]¹³C-NMR (δ, CDCl₃): 33.73, 41.61, 53.78, 55.79, 56.14, 58.82,60.57, 77.62, 102.43, 106.75, 114.73, 116.04 (d, J=21), 118.31, 120.65,127.79 (d, J=8), 136.36, 140.39, 151.96, 154.26, 155.16, 162.57 (d,J=246), 168.70.

[0367] MS (%): 470 (parent+1, 100).

[0368] HRMS Calc'd. for C₂₆H₂₉FNO₆: 470.1979. Found: 470.2000.

EXAMPLE 55({3-[3-Methoxy-4-(3-methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0369] Prepared as in Example 1, in 99% yield, as a foam.

[0370]¹³C-NMR (δ, CDCl₃): 33.44, 41.56, 53.99, 55.45, 56.13, 58.95,60.63, 78.07, 102.51, 102.69, 107.08, 107.64, 108.58, 122.39, 126.07,128.38, 129.14, 130.02, 138.39, 140.50, 152.52, 155.24, 160.01, 160.92,168.87.

[0371] MS (%): 452 (parent+1, 100).

[0372] HRMS Calc'd. for C₂₆H₃₀NO₆: 452.2073. Found: 452.2073.

EXAMPLE 56({3-[3-Methoxy-4-(4-methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0373] Prepared as in Example 1, in 100% yield, as a solid, mp 60.1° C.

[0374]¹³C-NMR (δ, CDCl₃): 33.47, 41.56, 53.97, 55.84, 56.16, 58.97,60.64, 78.08, 102.49, 106.90, 114.76, 118.28, 120.76, 126.07, 128.37,129.13, 140.22, 140.56, 151.99, 152.06, 154.50, 155.12, 168.76.

[0375] MS (%): 452 (parent+1, 100).

[0376] HRMS Calc'd. for C₂₆H₃₀NO₆: 452.2073. Found: 452.2081.

EXAMPLE 57({3-[4-(3-Methoxy-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0377] Prepared as in Example 1, in 92% yield, as a foam.

[0378]¹³C-NMR (δ, CDCl₃): 16.92, 29.65, 33.53, 41.57, 54.01, 55.53,58.71, 104.07, 108.16, 110.11, 113.93, 117.71, 122.54, 125.98, 128.36,128.64, 129.12, 130.18, 140.49, 149.93, 151.82, 159.73, 161.02, 168.59.

[0379] MS (%): 436 (parent+1, 100).

[0380] HRMS Calc'd. for C₂₆H₃₀NO₅: 436.2124. Found: 436.2103.

EXAMPLE 58{[3-[3-Methoxy-4-(3-methoxy-phenoxy)-phenoxy]-3-(4-methoxy-phenyl)-propyl]-methyl-amino}-aceticacid

[0381] Prepared as in Example 1, in 100% yield, as a foam.

[0382]¹³C-NMR (δ, CDCl₃): 29.65, 33.51, 41.69, 54.08, 55.49, 56.16,58.91, 77.77, 102.55, 102.72, 107.14, 107.64, 108.63, 114.54, 122.38,127.35, 130.03, 132.29, 138.39, 152.51, 155.23, 159.60, 160.04, 160.93,168.51.

[0383] MS (%): 482 (parent+1, 100).

[0384] HRMS Calc'd. for C₂₇H₃₂NO₇: 482.2179. Found: 482.2187.

EXAMPLE 59{[3-(3-Methoxy-4-phenoxy-phenoxy)-3-phenyl-propyl]-methyl-amino}-aceticacid

[0385] Prepared as in Example 1, in 98% yield, as a solid, mp 77.5° C.

[0386]¹³C-NMR (δ, CDCl₃): 29.64, 33.48, 41.57, 53.95, 56.10, 58.95,78.07, 102.46, 107.02, 116.42, 122.16, 126.03, 128.38, 129.13, 129.59,138.67, 140.51, 152.49, 155.12, 158.68, 168.75.

[0387] MS (%): 422 (parent+1, 100).

[0388] HRMS Calc'd. for C₂₅H₂₈NO₅: 422.1968. Found: 422.1972.

EXAMPLE 60{[3-(4-Fluoro-phenyl)-3-(3-methoxy-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0389] Prepared as in Example 1, in 100% yield, as a solid, mp 139.5° C.

[0390]¹³C-NMR (δ, CDCl₃): 33.79, 41.65, 53.80, 56.11, 58.83, 60.59,77.61, 102.46, 106.90, 116.08 (d, J=22), 116.44, 122.15, 122.22, 127.79(d, J=8), 129.60, 136.31, 136.34, 138.85, 152.53, 154.89, 158.63, 162.55(d, J=246), 168.67, 171.37.

[0391] MS (%): 440 (parent+1, 100).

[0392] HRMS Calc'd. for C₂₅H₂₇FNO₅: 440.1874. Found: 440.1876.

EXAMPLE 61{[3-(4-Fluoro-phenyl)-3-(2-methyl-4-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0393] Prepared as in Example 1, in 100% yield, as a foam.

[0394]¹³C-NMR (δ, CDCl₃): 16.90, 33.55, 41.48, 42.16, 53.93, 58.69,65.37, 77.00, 114.06, 116.10 (d, J=22), 117.50, 118.02, 122.37, 122.78,127.84 (d, J=7), 128.72, 129.81, 136.35, 150.38, 151.49, 158.33, 162.55(d, J=246), 168.76.

[0395] MS (%): 424 (parent+1, 100).

EXAMPLE 62{Methyl-[3-(2-methyl-4-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0396] Prepared as in Example 1, in 100% yield, as a foam.

[0397]¹³C-NMR (δ, CDCl₃): 16.94, 33.65, 41.46, 53.83, 58.79, 113.95,117.54, 117.98, 122.38, 122.67, 126.00, 128.33, 128.68, 129.11, 129.79,140.66, 150.19, 151.81, 158.46, 168.78.

[0398] MS (%): 406 (parent+1, 100).

EXAMPLE 63({3-[4-(4-Methoxy-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0399] Prepared as in Example 1, in 98% yield, as a foam.

[0400]¹³C-NMR (δ, CDCl₃): 16.96, 29.65, 33.63, 41.76, 54.14, 55.86,59.03, 112.50, 113.89, 114.91, 116.12, 119.99, 121.12, 125.97, 128.34,128.51, 129.12, 139.92, 140.54, 151.12, 151.42, 151.72, 155.57.

[0401] MS (%): 436 (parent+1, 100).

EXAMPLE 64({3-[4-(4-Chloro-phenoxy)-2-methyl-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0402] Prepared as in Example 1, in 100% yield, as a foam.

[0403]¹³C-NMR (δ, CDCl₃): 16.94, 33.54, 41.47, 53.90, 58.90, 114.01,117.58, 119.12, 122.36, 126.00, 127.53, 128.36, 128.82, 129.12, 129.70,140.54, 149.82, 152.01, 157.14, 168.88.

[0404] MS (%): 440 (parent+1, 100).

EXAMPLE 65{Methyl-[3-(2-methyl-4-p-tolyloxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0405] Prepared as in Example 1, in 100% yield, as a foam.

[0406]¹³C-NMR (δ, CDCl₃): 16.94, 20.85, 33.55, 41.43, 53.87, 58.85,113.97, 116.99, 118.24, 121.85, 126.05, 128.29, 128.57, 129.09, 130.28,132.27, 140.71, 150.83, 151.51, 155.98, 168.90.

[0407] MS (%): 420 (parent+1, 100).

EXAMPLE 66{[3-(2-Chloro-4-phenoxy-phenoxy)-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0408] Prepared as in Example 1, in 88.5% yield, as a foam.

[0409]¹³C-NMR (δ, CDCl₃): 33.74, 41.50, 53.62, 58.83, 78.85, 116.01 (d,J=21), 116.91, 118.20, 118.56, 121.19, 123.55, 124.21, 127.99 (d, J=8),129.96, 135.82, 135.85, 149.02, 151.38, 157.29, 162.55 (d,J=246),169.03, 171.28,

[0410] MS (%): 444 (parent+1, 100).

EXAMPLE 67{[3-(2-Chloro-4-p-tolyloxy-phenoxy)-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0411] Prepared as in Example 1, in 100% yield, as a solid, mp 129.3° C.

[0412]¹³C-NMR (δ, CDCl₃): 14.39, 33.58, 41.53, 53.70, 58.56, 78.85,116.02 (d, J=21), 117.01, 117.65, 118.86, 120.58, 124.17, 128.04 (d,J=8), 130.48, 133.29, 135.78, 135.81, 148.64, 152.13, 154.78, 162.62 (d,J=246), 168.84.

[0413] MS (%): 458 (parent+1, 100).

EXAMPLE 68{[3-[2-Chloro-4-(4-chloro-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0414] Prepared as in Example 1, in 100% yield, as a foam.

[0415]¹³C-NMR (δ, CDCl₃): 33.75, 41.60, 53.75, 58.70, 78.86, 116.11 (d,J=21), 116.92, 118.31, 119.77, 121.33, 124.36, 127.98 (d, J=9), 128.56,129.96, 135.66, 149.32, 151.00, 156.05, 162.68 (d, J=246), 168.81.

[0416] MS (%): 479 (parent+1, 100).

EXAMPLE 69 {Methyl-[3-(3-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-aceticacid

[0417] Prepared as in Example 1, in 95% yield, as a foam.

[0418]¹³C-NMR (δ, CDCl₃): 33.56, 41.45, 53.63, 58.52, 77.03, 77.36,77.67, 106.79, 110.83, 111.38, 119.34, 123.65, 126.01, 128.25, 129.08,129.95, 130.29, 140.26, 156.74, 158.49, 158.84, 168.75.

[0419] MS (%): 392 (parent+1, 100).

[0420] HRMS Calc'd. for C₂₄H₂₆NO₄: 392.1862. Found: 392.1866.

EXAMPLE 70{[3-(4-Fluoro-phenyl)-3-(3-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0421] Prepared as in Example 1, in 75% yield, as a foam.

[0422]¹³C-NMR (δ, CDCl₃): 33.70, 41.59, 53.69, 58.84, 60.61, 76.95,77.05, 77.27, 77.59, 106.75, 110.81, 111.51, 116.02 (d, J=22), 119.39,123.74, 127.79 (d, J=8), 129.95, 130.33, 136.08, 156.69, 158.61, 162.49(d, J=246), 168.70, 171.37.

[0423] MS (%): 410 (parent+1, 100).

[0424] HRMS Calc'd. for C₂₄H₂₅FNO₄: 410.1768. Found: 410.1788.

EXAMPLE 71{[3-(4-Fluoro-phenyl)-3-(3-p-tolyloxy-phenoxy)-propyl]-methyl-amino}-aceticacid A. 3-(4-Tolyl)oxy-phenol O-benzyl ether

[0425] Following Scheme II: To a 50 mL round-bottomed flask equippedwith gas inlet and reflux condenser were added 800 mg (4.0 mmol)3-benzyloxyphenol, 1.1 g (8.0 mmol) 4-tolyl boronic acid, 726 mg (4.0mmol) cupric acetate, 1.6 mL (20 mmol) dry pyridine, 900 mg molecularsieves, and 10 mL dry dimethylsulfoxide. The reaction was stirred underan atmosphere of dry oxygen at room temperature for 24 hr. The reactionwas then taken up in ethyl acetate, washed with several portions ofwater, washed with brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using hexane/ethyl acetate aseluant to afford 602 mg (52%) of the product as an oil.

[0426]¹H-NMR (δ, CDCl₃): 2.3 (s, 3H), 5.00 (m, 2H), 6.4-6.7 (m, 3H),(6.8-7.4 (m, 10H),

[0427] MS (%): 291 (parent+1, 100).

B. 3-(4-Tolyloxy)-phenol

[0428] Following Scheme II: To a 50 mL round-bottomed flask equippedwith reflux condenser and N₂ inlet were added 602 mg (2.07 mmol)3-(4-tolyloxy)-phenol-O-benzyl ether, 600 mg (15 mmol) ammonium formate,200 mg 20% palladium hydroxide on carbon, and 20 mL ethanol. Thereaction was reflxued for 1 hr, cooled, and filtered through Celite withethanol. The filtrate was concentrated and the residue chromatographedon silica gel using hexane/ethyl acetate as eluant to afford 185 mg(45%) of the product as an oil.

[0429]¹H-NMR (δ, CDCl₃): 2.33 (s, 3H), 6.45 (t, J=2, 1H), 6.53 (m, 2H),6.94 (m, 2H), 7.13 (m, 3H).

[0430]¹³C-NMR (δ, CDCl₃): 20.96, 105.70, 110.04, 110.69, 119.765,130.52, 130.60, 133.56, 154.37, 156.94, 159.47.

[0431] GC MS (%): 200 (parent, 100).

[0432] The remaining steps were carried out as in Example 1 to affordthe final product, with in 100% yield in the final step, as a foam.

[0433]¹³C-NMR (δ, CDCl₃): 20.94, 33.67, 41.54, 42.17, 53.71, 58.46,65.38, 106.29, 110.42, 111.02, 116.01 (d, J=21), 119.64, 127.81 (d,J=8), 130.26, 130.48, 133.47, 136.06, 136.09, 154.18, 158.59, 159.23,162.49 (d, J=246), 168.62.

[0434] MS (%): 424 (parent+1, 100).

[0435] HRMS Calc'd. for C₂₅H₂₇FNO₄: 424.1924. Found: 424.1917.

EXAMPLE 72({3-(4-Fluoro-phenyl)-3-[3-(4-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0436] Prepared as in Example 71, in 100% yield, as a foam.

[0437]¹³C-NMR (δ, CDCl₃): 29.65, 33.52, 41.56, 53.83, 55.82, 58.49,65.41, 105.61, 110.07, 110.36, 115.05, 116.01 (d, J=21), 121.29, 127.81(d, J=8), 130.24, 136.03, 149.58, 156.26, 158.55, 159.88, 162.48 (d,J=246), 168.6.

[0438] MS (%): 440 (parent+1, 100).

[0439] HRMS Calc'd. for C₂₅H₂₇FNO₅: 440.1873. Found: 440.1856.

EXAMPLE 73({3-[3-(4-Chloro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-aceticacid

[0440] Prepared as in Example 71, in 90% yield, as a foam.

[0441]¹³C-NMR (δ, CDCl₃): 33.68, 41.45, 53.59, 58.57, 60.59, 77.74,106.78, 111.24, 111.38, 117.46, 120.56, 125.97, 128.29, 128.58, 129.09,129.43, 129.90, 130.40, 140.22, 155.45, 158.14, 158.88, 168.75.

[0442] MS (%): 426 (parent+1, 100).

[0443] HRMS Calc'd. for C₂₄H₂₅ClNO₄: 426.1472. Found: 426.1476.

EXAMPLE 74{[3-[3-(4-Chloro-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0444] Prepared as in Example 71, in 77% yield, as a foam.

[0445]¹³C-NMR (δ, CDCl₃): 33.80, 41.61, 53.70, 58.78, 60.59, 77.57,106.73, 111.14, 111.50, 116.06 (d, J=22), 117.48, 120.65, 127.75 (d,J=8), 128.76, 129.50, 129.92, 130.45, 135.96, 155.37, 158.28, 158.65,162.52 (d, J=245), 168.62, 171.36.

[0446] MS (%): 444 (parent+1, 100).

[0447] HRMS Calc'd. for C₂₄H₂₄ClFNO₄: 444.1370. Found: 444.1355.

EXAMPLE 75({3-(4-Fluoro-phenyl)-3-[3-(2-methoxy-phenoxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0448] Prepared as in Example 71, in 53% yield, as a foam.

[0449]¹³C-NMR (δ, CDCl₃): 33.79, 41.02, 53.94, 56.04, 58.86, 60.60,105.03, 109.98, 110.14, 112.99, 116.00 (d, J=21), 121.30, 121.71, 127.74(d, J=8), 130.12, 136.05, 143.48, 144.47, 11.65, 158.50, 159.33, 162.47(d, J=245), 168.35.

[0450] MS (%): 440 (parent+1, 100).

[0451] HRMS Calc'd. for C₂₅H₂₇FNO₅: 440.1873. Found: 440.1852.

EXAMPLE 76{[3-(4-Fluoro-phenyl)-3-(4-methyl-3-phenoxy-phenoxy)-propyl]-methyl-amino}-aceticacid

[0452] Prepared as in Example 71, in 100% yield, as a foam.

[0453]¹³C-NMR (δ, CDCl₃): 33.32, 41.62, 53.95, 58.53, 60.64, 77.69,107.92, 111.70, 116.01 (J=21), 117.79, 122.57, 122.87, 127.92 (d, J=8),129.91, 131.84, 135.99, 136.02, 155.18, 156.34, 157.46, 162.49 (d,J=246), 168.72, 171.44, 174.59.

[0454] MS (%): 424 (parent+1, 100).

[0455] HRMS Calc'd. for C₂₅H₂₇FNO₄: 424.1924. Found: 424.1941.

EXAMPLE 77({3-(4-Fluoro-phenyl)-3-[3-(3-methoxy-phenoxy)-4-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0456] Prepared as in Example 71, in 100% yield, as a solid, mp 55-57°C.

[0457]¹³C-NMR (δ, CDCl₃): 15.49, 33.40, 41.47, 53.77, 55.45, 58.90,77.61, 103.92, 108.09, 108.33, 109.88, 111.87, 115.93 (d, J=22), 122.58,127.89 (d, J=8), 130.28, 131.81, 136.06, 154.95, 156.37, 158.68, 161.09,162.43 (d, J=246), 168.72.

[0458] MS (%): 454 (parent+1, 100).

EXAMPLE 78({3-(4-Fluoro-phenyl)-3-[3-(4-methoxy-phenoxy)-4-methyl-phenoxy]-propyl}-methyl-amino)-aceticacid

[0459] Prepared as in Example 71, in 100% yield, as a solid, mp 63-65°C.

[0460]¹³C-NMR (δ, CDCl₃): 15.55, 33.35, 41.38, 53.73, 55.78, 58.85,77.01, 106.18, 110.46, 114.96, 115.87 (d, J=22), 119.91, 121.44, 127.87(d, J=8), 131.60, 136.17, 136.20, 150.44, 155.66, 156.31, 156.62, 162.36(d, J=245), 168.76.

[0461] MS (%): 454 (parent+1, 100).

EXAMPLE 79{[3-[3-(Benzo[1,3]dioxol-5-yloxy)-4-methyl-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-aceticacid

[0462] Prepared as in Example 71, in 100% yield, as a solid, mp 185-188°C.

[0463]¹³C-NMR (δ, CDCl₃): 15.49, 33.59, 41.48, 53.67, 58.73, 60.59,76.98, 101.38, 101.66, 106.41, 108.35, 110.75, 110.93, 115.90 (d, J=21),121.54, 127.80 (d, J=8), 131.61, 136.13, 136.16, 143.55, 148.49, 151.75,156.32, 162.43 (d, J=246), 168.63.

[0464] MS (%): 468 (parent+1, 100).

EXAMPLE 80({3-(4-Fluoro-phenyl)-3-[4-(pyridin-2-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid A. 4-(Pyridin-2-yloxy)-benzaldehyde

[0465] Following Scheme I: Prepared as in Example 1 in 11.5% yield as anoil.

[0466]¹H-NMR (δ, CDCl₃): 6.99 (dd, J=1,8, 1H), 7.06 (m, 1H), 7.25 (m,2H), 7.75 (m, 1H), 7.89 (m, 2H), 8.21 (m, 1H), 9.95 (s, 1H).

[0467] MS (%): 200 (parent+1, 100).

B. 4-(Pyridin-2-yloxy)-phenol

[0468] Following Scheme I: To a 100 mL round-bottomed flask equippedwith condenser and N₂ inlet were added 3.1 g (50.2 mmol) boric acid, 10mL tetrahydrofuran, 2.3 mL (20 mmol) 30% hydrogen peroxide, and 1 mLconcentrated sulfuric acid. To the reaction was added a solution of 2.0g (10 mmol) 4-(pyridin-2-yloxy)-benzaldehyde in 10 mL tetrahydrofurandropwise over 5 minutes. The reaction was stirred 3 hr at 60° C.,cooled, filtered, and the filtrate neutralized with saturated aqueoussodium bicarbonate solution. The mixture was extracted into 2× ethylacetate, and the organic layer washed with brine, dried over sodiumsulfate, and evaporated. The residue was chromatographed on silica gelusing hexane/ethyl acetate as eluant to afford 180 mg (9.6%) of theproduct as a solid.

[0469]¹H-NMR (δ, CDCl₃): 6.72 (d, J=9, 2H), 6.87 (d, J=9, 2H), 6.9 (m,1H), 6.97 (m, 1H), 7.65 (m, 1H), 8.15 (m, 1H).

[0470]¹³C-NMR (δ, CDCl₃): 111.55, 117.17, 118.46, 122.38, 140,285,146.78, 147.21, 153.96, 164.55.

[0471] MS (%): 188 (parent+1, 100).

[0472] The remaining steps were carried out as in Example 1 with an 81%yield in the final step, as a foam.

[0473]¹³C-NMR (δ, CDCl₃): 33.60, 41.57, 53.85, 58.02, 111.42, 116.00 (d,J=22), 117.02, 118.48, 122.38, 127.89, (d, J=9), 136.26, 136.23, 139.60,147.67, 148.06, 154.27, 162.49 (d, J=245), 164.04, 168.61.

[0474] MS (%): 411 (parent+1, 100).

[0475] HRMS Calc'd. for C₂₃H₂₄FN₂O₄: 411.1720. Found: 411.1747.

EXAMPLE 81(Metyhl-{3-phenyl-3-[4-(pyridin-3-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0476] Prepared as in Example 80, in 39% yield, as a foam.

[0477]¹³C-NMR (δ, CDCl₃): 33.75, 41.69, 53.88, 58.49, 78.18, 117.45,120.78, 124.24, 124.64, 126.03, 128.43, 129.16, 140.28, 140.57, 143.81,149.83, 154.32, 154.92, 168.58.

[0478] MS (%): 393 (parent+1, 100).

[0479] HRMS Calc'd. for C₂₃H₂₅N₂O₄: 393.1814. Found: 393.1804.

EXAMPLE 82(Methyl-{3-phenyl-3-[4-(pyridin-4-yloxy)-phenoxy]-propyl}-amino)-aceticacid

[0480] Prepared as in Example 80, in 34% yield, as a foam.

[0481]¹³C-NMR (δ, CDCl₃): 33.82, 41.77, 53.93, 59.03, 78.22, 111.93,117.45, 122.10, 126.00, 128.42, 129.15, 140.31, 147.63, 151.14, 155.17,165.54, 169.02.

[0482] MS (%): 393 (parent+1, 100).

EXAMPLE 83({3-(4-Fluoro-phenyl)-3-[4-(pyridin-3-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0483] Prepared as in Example 80, in 65% yield, as a foam.

[0484]¹³C-NMR (δ, CDCl₃): 33.70, 41.79, 53.99, 59.06, 60.59, 116.08 (d,J=21), 117.46, 120.76, 124.27, 124.77, 127.83 (d, J=8), 136.07, 140.44,143.76, 149.95, 154.08, 154.85, 162.54 (d, J=246), 168.88.

[0485] MS (%): 411 (parent+1, 100).

[0486] HRMS Calc'd. for C₂₃H₂₄FN₂O₄: 411.1720. Found: 411.1747.

EXAMPLE 84({3-(4-Fluoro-phenyl)-3-[4-(pyridin-4-yloxy)-phenoxy]-propyl}-methyl-amino)-aceticacid

[0487] Prepared as in Example 80, in 25% yield, as a foam.

[0488]¹³C-NMR (δ, CDCl₃): 34.05, 41.79, 53.82, 59.01, 111.93, 116.11 (d,J=22), 117.48, 122.14, 127.84 (d, J=9), 136.13, 147.79, 151.23, 154.97,162.56 (d, J=246), 165.46, 169.14.

[0489] MS (%): 411 (parent+1, 100).

What is claimed is:
 1. A compound of the formula I

wherein ring A is phenyl, naphthyl, benzothienyl, benzofuranyl, orpyridyl; or ring A is a monocyclic aryl or heteroaryl ring containingfrom zero to four heteroatoms and not containing any adjacent ringoxygen atoms; or ring A is a bicyclic aryl or heteroaryl ring containingfrom zero to five heteroatoms and not containing any adjacent ringoxygen atoms; and X and Y are each, independently, (C₁-C₆)alkyloptionally substituted with from one to seven fluorine atoms;(C₁-C₆)alkoxy optionally substituted with from one to seven fluorineatoms, wherein the number of fluorine substituents on the foregoing(C₁-C₆)alkyl and (C₁-C₆) alkoxy groups can not exceed the number ofpositions in such groups that are available for substitution; carboxy;carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl; sulfonyl;halo; nitro; cyano; amino; (C₁-C₆) alkylamino and di{(C₁-C₆)alkyl}amino;B is (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with 1 to 7fluorine atoms, or halogen; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, wherein ring A is selectedfrom phenyl, benzofuranyl and pyridyl.
 3. A compound according to claim2, wherein Y is selected from fluoro, bromo, chloro, methyl, ethyl,methoxy, ethoxy, phenyl, benzyl, and acetyl.
 4. A compound according toclaim 1, wherein X is 4-trifluoromethyl, 4-methyl, methoxy, phenyl,benzyl, or 4-chloro.
 5. A compound having the formula:

wherein X and Y are each, independently, (C₁-C₆)alkyl optionallysubstituted with from one to seven fluorine atoms; (C₁-C₆)alkoxyoptionally substituted with from one to seven fluorine atoms, whereinthe number of fluorine substituents on the foregoing (C₁-C₆)alkyl and(C₁-C₆) alkoxy groups can not exceed the number of positions in suchgroups that are available for substitution; carboxy;carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl; sulfonyl;halo; nitro; cyano; amino; (C₁-C₆) alkylamino and di[(C₁-C₆)alkyl]amino;or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 5, wherein X is selected from 2-fluoro, 4-fluoro, 4-chloro,trifluoromethyl, acetyl, 2-methyl, 4-methyl, 4-methoxy, phenyl, phenoxy,naphthyl and benzothienyl; or, wherein Y is selected from hydrogen,fluoro, chloro, methyl, and methoxy.
 7. A compound having the formula:

wherein Y is (C₁-C₆)alkyl optionally substituted with from one to sevenfluorine atoms; (C₁-C₆)alkoxy optionally substituted with from one toseven fluorine atoms, wherein the number of fluorine substituents on theforegoing (C₁-C₆)alkyl and (C₁-C₆) alkoxy groups can not exceed thenumber of positions in such groups that are available for substitution;carboxy; carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl;sulfonyl; halo; nitro; cyano; amino; (C₁-C₆) alkylamino anddi{(C₁-C₆)alkyl}amino; wherein Z₁ and Z₂ are independently selected fromO, NH, N—(C₁-C₅ alkyl), and S; and n is an integer from 1 to about 3; ora pharmaceutically acceptable salt thereof.
 8. The compound according toclaim 7, wherein Y is selected from hydrogen, 2-fluoro,4-trifluoromethyl, 4-fluoro, 4-chloro, 2-methyl, 4-methyl, 4-methoxy,naphthyl and benzothienyl.
 9. The compound according to claim 7, whereinZ₁ and Z₂ are each O; and n is 1 or
 2. 10. A compound having theformula:

wherein Y is (C₁-C₆)alkyl optionally substituted with from one to sevenfluorine atoms; (C₁-C₆)alkoxy optionally substituted with from one toseven fluorine atoms, wherein the number of fluorine substituents on theforegoing (C₁-C₆)alkyl and (C₁-C₆) alkoxy groups can not exceed thenumber of positions in such groups that are available for substitution;carboxy; carbo-(C₁-C₆)alkoxy; carboxamido; (C₁-C₆)alkyl-thio; sulfoxyl;sulfonyl; halo; nitro; cyano; amino; (C₁-C₆) alkylamino anddi{(C₁-C₆)alkyl}amino; wherein Z₁ and Z₂ are independently selected fromO, NH, N—(C₁-C₅ alkyl), and S; and n is an integer from 1 to about 3; ora pharmaceutically acceptable salt thereof.
 11. The compound accordingto claim 10, wherein Y is selected from hydrogen, 2-fluoro,4-trifluoromethyl, 4-fluoro, 4-chloro, 2-methyl, 4-methyl, 4-methoxy,naphthyl and benzothienyl; or wherein Z₁ and Z₂ are each O, and n is 1or 2; and Y is H, F, or Cl.
 12. A method of treating a disorder orcondition selected from psychosis, schizophrenia, conduct disorder,disruptive behavior disorder, bipolar disorder, psychotic episodes ofanxiety, anxiety associated with psychosis, psychotic mood disordersselected from severe major depressive disorder; mood disordersassociated with psychotic disorders selected from acute mania,depression associated with bipolar disorder and mood disordersassociated with schizophrenia; behavioral manifestations of mentalretardation, conduct disorder and autistic disorder; movement disordersselected from Tourette's syndrome, akinetic-rigid syndrome, movementdisorders associated with Parkinson's disease, tardive dyskinesia, andother drug-induced and neurodegeneration-based dyskinesias; attentiondeficit hyperactiyity disorder; cognitive disorders selected fromdementias, age-related dementia and senile dementia of the Alzheimer'stype; and memory disorders in a mammal, comprising administering to amammal in need of such treatment an amount of a compound of according toclaim 1 that is effective in treating such condition or disorder.
 13. Apharmaceutical composition for treating a disorder or condition selectedfrom psychosis, schizophrenia, conduct disorder, disruptive behaviordisorder, bipolar disorder, psychotic episodes of anxiety, anxietyassociated with psychosis, psychotic mood disorders selected from severemajor depressive disorder; mood disorders associated with psychoticdisorders selected from acute mania and depression associated withbipolar disorder, and mood disorders associated with schizophrenia;behavioral manifestations of mental retardation, conduct disorder andautistic disorder; movement disorders selected from Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia and other drug-induced andneurodegeneration-based dyskinesias; attention deficit hyperactiyitydisorder; cognitive disorders selected from dementias, age-relateddementia and senile dementia of the Alzheimer's type; and memorydisorders in a mammal, comprising an amount of a compound according toclaim 1 that is effective in treating such disorder or condition.
 14. Amethod of treating a disorder or condition selected from psychosis,schizophrenia, conduct disorder, disruptive behavior disorder, bipolardisorder, psychotic episodes of anxiety, anxiety associated withpsychosis, psychotic mood disorders selected from severe majordepressive disorder; mood disorders associated with psychotic disordersselected from acute mania and depression associated with bipolardisorder, and mood disorders associated with schizophrenia; behavioralmanifestations of mental retardation, conduct disorder and autisticdisorder; movement disorders selected from Tourette's syndrome,akinetic-rigid syndrome, and movement disorders associated withParkinson's disease, tardive dyskinesia, and other drug-induced andneurodegeneration-based dyskinesias; attention deficit hyperactiyitydisorder; cognitive disorders selected from dementias, age-relateddementia, and senile dementia of the Alzheimer's type; and memorydisorders in a mammal, including a human, comprising administering to amammal in need of such treatment a glycine transport inhibiting amountof a compound according to claim
 1. 15. A pharmaceutical composition fortreating a disorder or condition selected from psychosis, schizophrenia,conduct disorder, disruptive behavior disorder, bipolar disorder,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders selected from severe major depressive disorder;mood disorders associated with psychotic disorders selected from acutemania and depression associated with bipolar disorder, and mooddisorders associated with schizophrenia; behavioral manifestations ofmental retardation, conduct disorder and autistic disorder; movementdisorders selected from Tourette's syndrome, akinetic-rigid syndrome,movement disorders associated with Parkinson's disease, tardivedyskinesia and other drug-induced and neurodegeneration-baseddyskinesias; attention deficit hyperactiyity disorder; cognitivedisorders selected from dementias, age-related dementia and seniledementia of the Alzheimer's type; and memory disorders in a mammal,including a human, comprising a glycine transport-inhibiting amount of acompound according to claim 1.